Allogeneic stem cell transplantation (alloHCT) is an effective therapy for persons with acute myeloid leukemia (AML). Despite this, relapse occurs in 30-40% of patients transplanted for AML and is the leading cause of death in this population. There is an urgent need to decrease the risk of AML relapse following alloHCT. Natural killer (NK) cells are bone marrow-derived lymphocytes whose effector function is mediated by interaction between NK cell surface killer immunoglobulin-like receptors (KIR) and their cognate HLA class I ligands on target cells. Donor-derived NK cells are known to exhibit a strong graft versus leukemia effect after alloHCT, preventing disease relapse. Thus, maximizing donor NK alloreactivity is an attractive goal for improving post-alloHCT outcomes. Similar to HLA, the KIR genes are highly diverse both in terms of variable gene content between individuals as well as allelic polymorphism within KIR gene loci. KIR and HLA combinatorial diversity creates a spectrum of NK reactivity that varies between individuals, resulting in differences in anti-tumor potency and HLA class I-mediated inhibition. Large retrospective clinical studies have demonstrated that donor KIR/HLA combinations dictating higher NK response and lower sensitivity to inhibition are associated with diminished risk for relapse following alloHCT for AML A novel algorithm based on KIR/HLA gene and allele combinations can be used to distinguish KIR-advantageous stem cell donors from otherwise HLA-equivalent donors for patients needing alloHCT. The proposed study will demonstrate in a prospective multicenter clinical trial for AML patients requiring an alloHCT from an unrelated donor that (1) KIR/HLA combinations can be used to identify and select KIR-advantageous donors, and (2) patients with KIR-advantageous donors will have less relapse and higher survival. Correlative laboratory studies using fluorescence and mass cytometry will demonstrate that donor-derived NK cells exhibit higher NK activity and less inhibition in response to leukemia target cells when their KIR and HLA genotypes imply advantage(s). Combined, these studies have the potential to transform current donor selection practices and reduce the risk of leukemia relapse in patients.